There is a pressing need for new therapeutics for HIV/AIDS. Although currently available antiretroviral drugs can control viral replication and delay the onset of immune failure in most HIV-infected individuals, they do not completely eliminate the virus. Furthermore, there are no effective biomedical treatments to prevent new infections, which continue to accelerate world-wide. We are using molecular biology, protein engineering, and rational drug design to develop new therapeutics and preventatives for HIV. One project is to develop a strategy that will reduce the size of the latent reservoir of HIV that is responsible for viral persistence. This is accomplished by using synthetic analogues of diacylglycerol to induce the expression of latent infectious virus, then killing the induced cells with targeted toxins that bind to the viral envelope protein. A second project is to develop live microbes that can prevent new HIV infections by secreting anti-HIV peptides onto the mucosal surfaces of the vagina and rectum, the major sites of HIV transmission.. We have demonstrated the feasibility of this live microbicide approach by genetically engineering a commensal strain of bacteria to secrete high levels of an HIV fusion inhibitor both in vitro and in vivo.